In its briefing document for Thursday’s FDA advisory committee meeting, the regulator contends that the company’s confirmatory CodeBreaK 200 trial for Lumakras is not an “adequate and well-controlled” study.
Pictured: FDA headquarters/iStock, Grandbrothers
Amgen’s regulatory ambitions for its non-small cell lung cancer drug Lumakras (sotorasib) ran into headwinds Tuesday, after FDA staff indicated in their briefing document that there might not be sufficient evidence of its efficacy to justify full approval.
The news comes before the FDA’s Oncologic Drugs Advisory Committee is slated to meet on Thursday to discuss Amgen’s supplemental New Drug Application seeking full approval of sotorasib in non-small cell lung cancer.
Sotorasib, an oral inhibitor of G12C-mutated KRAS marketed as Lumakras, was originally given accelerated approval by the FDA in May 2021 for advanced lung cancer patients with KRAS mutations that either didn’t respond, or stopped responding, to an initial treatment. The follow-up study recently reviewed by the regulator was required as a condition for the drug’s accelerated approval.
Amgen submitted the results of the Phase III CodeBreaK 200 trial of sotorasib versus docetaxel to verify the clinical benefit of the KRAS inhibitor and support its conversion from accelerated to traditional approval.
The CodeBreaK 200 trial was marred by what FDA staff described in their briefing document released on Tuesday as “multiple sources of systemic bias, raising concerns about whether CodeBreaK 200 can be considered an adequate and well-controlled trial.” These included greater patient dropout from those receiving the docetaxel versus sotorasib, “investigator assessments of progressive disease favoring the sotorasib arm,” and patient crossover from docetaxel to sotorasib “before assessment of disease progression” via blinded independent central review (BICR).
FDA staff also suggested that the study’s primary endpoint of progression-free survival may not be reliable “given its magnitude relative to the imaging interval (five weeks versus six weeks).”
Though the data did show an improvement in risk of disease progression of 34% in patients with advanced lung cancer, this was comparable to chemotherapy. In addition, there was no significant difference in overall survival, though Amgen noted the trial was not intended to detect a difference.
The drug targets G-12C-mutated KRAS, which occurs in about 13% of non-small cell lung cancers (NSCLC) and in approximately 85% of all lung cancers diagnosed each year.
“Give the longstanding knowledge,” of this mutation, and “the multiple failed attempts to develop effective drugs in this space, the early promising results of CodeBreaK 100 were met with great enthusiasm by the oncology community,” FDA staff noted in the briefing document.
However, the regulator made the case that “issues in study conduct, high rates of censoring, loss of follow up of patients who withdrew consent, and potential loss of randomization may not allow for adequate analysis of the results of CodeBreaK 200.”
On that basis, the FDA requested in its briefing document that the adcomm’s discussion on Thursday be focused on “whether the results of CodeBreaK 200 can be reliably interpreted and whether CodeBreaK 200 can be considered an adequate and well-controlled trial.”
The news put a mild damper on Amgen’s stock price, according to Reuters, which reported a 1.3% drop to $262.92 per share.
The FDA is expected to make a final decision on or before Dec. 24.
Connor Lynch is a freelance writer based in Ottawa, Canada. Reach him at lynchjourno@gmail.com.
